Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor
Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor
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DOI：
10.1016/j.clim.2009.01.002
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发表时间：
2009-05-01
影响因子：
8.6
通讯作者：
Sasso, Eric H.
中科院分区：
文献类型：
--
作者：
Kaymakcalan, Zehra;Sakorafas, Paul;Sasso, Eric H.
TNF拮抗剂阿达木单抗、英夫利昔单抗和依那西普可有效治疗类风湿性关节炎、银屑病关节炎、强直性脊柱炎和银屑病，但仅阿达木单抗和英夫利昔单抗被发现对克罗恩病有效。目前的研究评估了阿达木单抗、英夫利昔单抗和依那西普的 TNF 结合和补体激活特性，以确定这些特性是否可以解释它们临床疗效特征的差异。通过表面等离子共振测量与可溶性 TNF 结合的结合率和解离率，发现阿达木单抗、英夫利昔单抗和依那西普的结合率和解离率相似，计算出的结合亲和力也相似。通过 KinExA (R) 技术测量，可溶性依那西普 (K(D)=0.4 皮摩尔 [pM]) 与可溶性 TNF 的结合亲合力比可溶性阿达木单抗或英夫利昔单抗 (K(D)=8.6 和 4.2 pM) 高 10 至 20 倍。 (125)I-阿达木单抗、-英夫利昔单抗和-依那西普以相似的亲和力（分别为 K(D)=483、468 和 445 pM）与 mTNF 转染细胞上的膜 TNF (mTNF) 结合，且各自比可溶性 TNF 更高。阿达木单抗和英夫利昔单抗在 mTNF 转染细胞中诱导补体依赖性细胞毒性 (CDC)，但 3 种药物中的任何一种均未在活化的正常人 PBMC 中诱导补体依赖性细胞毒性 (CDC)。总之，阿达木单抗、英夫替昔单抗和依那西普对可溶性 TNF 的结合特性相似，对 mTNF 的结合特性非常相似，但三者均不能在活化的 PBMC 中诱导 CDC。这些结果表明，这些药物的不同临床疗效特征不能用 TNF 内在结合特性或补体裂解的差异来解释。 (C) 爱思唯尔公司。保留所有权利。
The TNF antagonists adalimumab, infliximab, and etanercept are effective treatments for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis, but only adalimumab and infliximab have been found to be efficacious in Crohn's disease. The present studies evaluated the TNF-binding and complement-activating properties of adalimumab, infliximab, and etanercept to determine whether these properties may explain differences in their clinical efficacy profiles. Association and dissociation rates of binding to soluble TNF were measured by surface plasmon resonance, and were found to be similar for adalimumab, infliximab, and etanercept, as were their calculated binding affinities. Avidity of binding to soluble TNF, measured by KinExA (R) technotogy, was 10- to 20-fold greater for soluble etanercept (K(D)=0.4 picomolars [pM]) than for soluble adalimumab or infliximab (K(D)=8.6 and 4.2 pM, respectively). (125)I-adalimumab, -infliximab, and -etanercept bound to membrane TNF (mTNF) on mTNF-transfected cells with similar affinities (K(D)=483, 468, and 445 pM, respectively) that were each tower than for soluble TNF. Complement-dependent cytotoxicity (CDC) was induced in mTNF-transfected cells by adalimumab and infliximab, but was not induced in activated normal human PBMC by any of the 3 agents. In conclusion, the binding properties of adatimumab, inftiximab, and etanercept were similar for soluble TNF, and very similar for mTNF, yet none of the 3 was able to induce CDC in activated PBMC. These results suggest that the different clinical efficacy profiles of these agents are not explained by differences in either TNF-intrinsic binding properties or complement lysis. (C) Elsevier Inc. All rights reserved.